Registration Dossier

no study available

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: scientifically acceptable and well documented pilot study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Dimethyl propylphosphonate was investigated in a limited but reliable fertility test in rats, initially performed as a pilot study for further testing. In this test dimethyl propylphosphonate was administered daily via gavage in corn oil to 5 male and 5 female Wistar rats (HsdRCCHan:Wist) per dose group at dose levels of 0, 20, 100 and 500 mg/kg body weight. The treatment started 2 weeks prior to the two weeks mating period. Male rats were treated up to necropsy (for a total period of 44 days). Female rats were treated up to necropsy on PND 4 (a total period of 6 to 7 weeks). Evaluation included general tolerance of dimethyl propylphosphonate by the parental animals as well as effects on reproduction including early postnatal development of F1 pups. The animals were regularly observed and weighed, food/water intake and reproduction parameters were determined. Organs were investigated macroscopically. In addition, kidneys were collected for histopathological investigations because alpha-2-microglobulin nephropathy was observed in the repeated dose experiments performed earlier.

GLP compliance:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on mating procedure:

The premating period took 14 days up to the cohabitation period. During the following two week cohabitation period the first FO male was co-housed with the first female within the group and so on over night (afternoon up to next morning). The co-housing period took 5 days. lnseminated females were not further co-housed as a rule. Insemination was established by investigating vaginal smears prepared in the morning after co-housing or by occurring of a vaginal plug.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

male rats: 44 days
female rats: 6-7 weeks

Frequency of treatment:

once daily

Details on study schedule:

The treatment started 2 weeks prior to the two weeks mating period. Male rats were treated up to necropsy (for a total period of 44 days). Female rats were treated up to necropsy on PND 4 (a total period of 6 to 7 weeks).

Remarks:

Doses / Concentrations:
0, 20, 100, or 500 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

5 male and 5 female rats/dose

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: At 500 mg/kg reduced body weight, increased food intake and kidney effects were observed.

Dose descriptor:

LOEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Kiney effects (alpha-2- microglobulin nephropathy) were observed in males at all dose groups; these effects are species and gender specific and not relevant for human risk assessment.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: At 500 mg/kg effects in number of pups, sex ratio and litter size, viability and live birth index were observed.

Reproductive effects observed:

not specified

Mortality in parental animals was not affected by the test substance but no pup survived a treatment of the dams with 500 mg/kg.

No remarkable clinical findings were observed at daily detailed clinical observations up to 500 mg/kg.

Body weight gain was statistically significantly reduced in high-dosed females during GD 14 to GD 20.

Animals of the 500 mg/kg group showed a significantly higher food intake in week 5 and 6 (males) andin week 2 of premating (females).

High dosed females showed a higher food consumption during gestation period.

No remarkable effects on water consumption were seen in all males and females up to 500 mg/kg.

Necropsy revealed pelvic dilation of the kidneys in 4/5 females, which was microscopically confirmed in 3 out of 4 diagnosed females at 500 mg/kg. In one female this finding was cornbined with tubular dilation and degeneration, papillary necrosis, pelvic degeneration and transitional cell hyperplasia.

Male kidneys showed an increase of cortical basophilic tubules tagether with tubular dilation starting at 20 mg/kg. Furthermore, cortical tubules revealed swelling and/or vacuolation at 20 mg/kg and above, tubular degeneration and debris was found in 20 and 100 mg/kg males. Hyaline droplets increased at 100 mg/kg and above. Pelvic dilation with urothelial degeneration occurred in one male at 20 mg/kg.

Results of reproduction parameters showed that insemination and gestation indices as well as the mean duration of gestation did not differ compared to control animals. A low fertility index ( 60%) and a lower number of females with live born pups were seen in 500 mg/kg.

The mating performance was not influenced by the treatment up to 500 mg/kg.

In high-dosed females less implantation sites and 64% less total number of pups related to implantation sites were observed, so that the prenatal loss was increased in this group.

At 500 mg/kg effects in number of pups, sex ratio and litter size, viability and live birth index could be observed.

No clinical signs could be observed in F1 pups during the five days lactation period at doses up to 100 mg/kg. No pup of the 500 mg/kg group survived PND 1. Two pups of dam No. 38 died on PND 0, one pup was cannibalized, noticed on PND 1. All pups of dam No. 39 were cannibalized, established on PND 1. One pup of uncertain sex and status of dam No. 40 was seen but could not be found anymore, after parturition was fmished.

Pup weights at birth and on PND 4 were not toxicologically relevantly changed up to 100 mg/kg. Slightly lower pup weights were seen on PND 0 at 500 mg/kg but without statistical significance.

No treatrnent related macroscopical alterations were noted at pup necropsies up to 100 mg/kg. One pup of the 100 mg/kg group revealed hydronephrosis of the left kidney. This finding was not observed in other pups and is a frequently appearing effect in Wistar rats. At 500 mg/kg only three pups could be necropsied. One stillbom revealed no finding and in the stomach of two dead pups no milk was found.

Executive summary:

Dimethyl propylphosphonate (DMPP) was administered daily via gavage in corn oil to 5 male and 5 female Wistar rats (HsdRCCHan:Wist) per dose group at dose levels of 0, 20, 100 and 500 mg/kg body weight. The treatment started 2 weeks prior to the two weeks mating period. Male rats were treated up to necropsy (for a total period of 44 days). Female rats were treated up to necropsy on PND 4 (a total period of 6 to 7 weeks).

Evaluation included general tolerance of dimethyl propylphosphonate by the parental animals as well as effects on reproduction including early postnatal development of F1 pups. The animals were regularly observed and weighed, food/water intake and reproduction parameters were determined.

Organs were investigated macroscopically. In addition, kidneys were collected for histopathological investigations.

Mortality in parental animals was not affected by dimethyl propylphosphonate but no pup survived a treatment of the dams with 500 mg/kg.

No remarkable clinical findings were observed at daily detailed clinical observations up to 500 mg/kg.

Body weight gain was statistically significantly reduced in high-dosed females during GD 14 to GD 20.

Animals of the 500 mg/kg group showed a significantly higher food intake in week 5 and 6 (males) and in week 2 of premating (females).

High dosed females showed a higher food consumption during gestation period.

No remarkable effects on water consumption were seen in all males and females up to 500 mg/kg.

Necropsy revealed pelvic dilation of the kidneys in 4/5 females, which was microscopically confirmed in 3 out of 4 diagnosed females at 500 mg/kg. In one female this finding was cornbined with tubular dilation and degeneration, papillary necrosis, pelvic degeneration and transitional cell hyperplasia.

Male kidneys showed an increase of cortical basophilic tubules tagether with tubular dilation starting at 20 mg/kg. Furthermore, cortical tubules revealed swelling and/or vacuolation at 20 mg/kg and above, tubular degeneration and debris was found in 20 and 100 mg/kg males. Hyaline droplets increased at 100 mg/kg and above. Pelvic dilation with urothelial degeneration occurred in one male at 20 mg/kg.

Results of reproduction parameters showed that insemination and gestation indices as well as the mean duration of gestation did not differ compared to control animals. A low fertility index ( 60%) and a lower number of females with live bom pups were seen in 500 mg/kg.

The mating performance was not influenced by the treatment up to 500 mg/kg.

In high-dosed females less implantation sites and 64% less total number of pups related to implantation sites were observed, so that the prenatal loss was increased in this group.

At 500 mg/kg effects in number of pups, sex ratio and litter size, viability and live birth index could be observed.

No clinical signs could be observed in F1 pups during the five days lactation period at doses up to 100 mg/kg. No pup of the 500 mg/kg group survived PND 1. Two pups of dam No. 38 died on PND 0, one pup was cannibalized, noticed on PND 1. All pups of dam No. 39 were cannibalized, established on PND 1. One pup of uncertain sex and status of dam No. 40 was seen but could not be found anymore, after parturition was fmished.

Pup weights at birth and on PND 4 were not toxicologically relevantly changed up to 100 mg/kg. Slightly lower pup weights were seen on PND 0 at 500 mg/kg but without statistical significance.

No treatment related macroscopical alterations were noted at pup necropsies up to 100 mg/kg. One pup of the 100 mg/kg group revealed hydronephrosis ofthe left kidney. This finding was not observed in other pups and is a frequently appearing effect in Wistar rats. At 500 mg/kg only three pups could be necropsied. One stillborn revealed no finding and in the stomach of two dead pups no milk was found.

Taken all together a no-observed-(adverse)-effect-level (NOAEL) cannot be determined for male rats. For females it is assigned at 100 mg/kg dimethyl propylphosphonate orally. The NOAEL for fertility is assigned at 100 mg/kg for male and female parental rats and 100 mg/kg for the male and female pups.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The materials/methods and results are described in detail und are sufficient for evaluation

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Dimethyl propylphosphonate (DMPP) was investigated in a limited but reliable fertility test in rats, initially performed as a pilot study for further testing. In this test dimethyl propylphosphonate was administered daily via gavage in corn oil to 5 male and 5 female Wistar rats (HsdRCCHan:Wist) per dose group at dose levels of 0, 20, 100 and 500 mg/kg body weight. The treatment started 2 weeks prior to the two weeks mating period. Male rats were treated up to necropsy (for a total period of 44 days). Female rats were treated up to necropsy on PND 4 (a total period of 6 to 7 weeks). Evaluation included general tolerance of dimethyl propylphosphonate by the parental animals as well as effects on reproduction including early postnatal development of F1 pups. The animals were regularly observed and weighed, food/water intake and reproduction parameters were determined. Organs were investigated macroscopically. In addition, kidneys were collected for histopathological investigations because alpha-2-microglobulin nephropathy was observed in the repeated dose experiments performed earlier.

Mortality in parental animals was not affected by dimethyl propylphosphonate but no pup survived a treatment of the dams with 500 mg/kg. No remarkable clinical findings were observed at daily detailed clinical observations up to 500 mg/kg.

Body weight gain was statistically significantly reduced in high-dosed females during GD 14 to GD 20. Animals of the 500 mg/kg group showed a significantly higher food intake in week 5 and 6 (males) and in week 2 of premating (females). High dosed females showed a higher food consumption during gestation period.

No remarkable effects on water consumption were seen in all males and females up to 500 mg/kg.

Male kidneys showed an increase of cortical basophilic tubules together with tubular dilation starting at 20 mg/kg. Furthermore, cortical tubules revealed swelling and/or vacuolation at 20 mg/kg and above, tubular degeneration and debris was found in 20 and 100 mg/kg males. Hyaline droplets increased at 100 mg/kg and above. Pelvic dilation with urothelial degeneration occurred in one male at 20 mg/kg.

Necropsy revealed pelvic dilation of the kidneys in 4/5 females, which was microscopically confirmed in 3 out of 4 diagnosed females at 500 mg/kg. In one female this finding was combined with tubular dilation and degeneration, papillary necrosis, pelvic degeneration and transitional cell hyperplasia.

Results of reproduction parameters showed that insemination and gestation indices as well as the mean duration of gestation did not differ compared to control animals. A low fertility index ( 60%) and a lower number of females with live born pups were seen in 500 mg/kg. The mating performance was not influenced by the treatment up to 500 mg/kg.

In high-dosed females less implantation sites and 64% less total number of pups related to implantation sites were observed, so that the prenatal loss was increased in this group. At 500 mg/kg effects in number of pups, sex ratio and litter size, viability and live birth index could be observed.

No clinical signs could be observed in F1 pups during the five days lactation period at doses up to 100 mg/kg. No pup of the 500 mg/kg group survived PND 1. Two pups of dam No. 38 died on PND 0, one pup was cannibalized, noticed on PND 1. All pups of dam No. 39 were cannibalized, established on PND 1. One pup of uncertain sex and status of dam No. 40 was seen but could not be found anymore, after parturition was finished.

Pup weights at birth and on PND 4 were not toxicologically relevantly changed up to 100 mg/kg. Slightly lower pup weights were seen on PND 0 at 500 mg/kg but without statistical significance.

No treatment related macroscopical alterations were noted at pup necropsies up to 100 mg/kg. One pup of the 100 mg/kg group revealed hydronephrosis of the left kidney. This finding was not observed in other pups and is a frequently appearing effect in Wistar rats. At 500 mg/kg only three pups could be necropsied. One stillborn revealed no finding and in the stomach of two dead pups no milk was found.

Taken together, for male rats kidney observations are reported in all dose groups based on alpha-2-microglobulin nephropathy, a mechanism not relevant for humans. The NOAEL for females is assigned at 100 mg/kg. The NOAEL for fertility is assigned at 100 mg/kg for male and female parental rats and 100 mg/kg for the male and female pups.

Short description of key information:
In a limited but reliable reproduction/developmental toxicity test dimethyl propylphosphonate was administered daily via gavage in corn oil to 5 male and 5 female Wistar rats per dose group at dose levels of 0, 20, 100 and 500 mg/kg body weight. The treatment started 2 weeks prior to the two weeks mating period. Male rats were treated up to necropsy (for a total period of 44 days). Female rats were treated up to necropsy on PND 4 (a total period of 6 to 7 weeks). Male rats in all dose groups showed kidney effects related to alpha-2-microglobulin nephropathy, a toxicological mechanism not relevant for humans. Alpha-2-microglobulin nephropathy independent systemic toxicity was seen at 500 mg/kg in females; reduced body weight and increased food consumption. At 500 mg/kg effects on fertility were observed; reduced number of pups and litter size, sex ratio, viability and live birth index.

Justification for selection of Effect on fertility via oral route:
The most reliable study was used as key study and for classification

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

In a limited but reliable reproduction/developmental toxicity test with dimethyl propylphosphonate effects on fertility were observed; reduced number of pups and litter size, sex ratio, viability and live birth index. Based on this study dimethyl propylphosphonate will be labeled according to GHS criteria with Repr. Cat 1B; H360 (may damage fertility or the unborn child).